Abstract 13534: Upregulation of NOX4 Triggers Mitochondrial Dysfunction During the Progression of Infant Right Ventricular Hypertrophy to Failure
Background: Right ventricular failure (RVF) due to abnormal hemodynamic load occurs frequently and is the cause of poor outcome and death in many forms of congenital heart disease and pulmonary hypertension. We have previously reported that early and progressive mitochondrial dysfunction is a likely cause of RVF in the pressure-loaded infant right ventricle. NADPH oxidase-4 (NOX4) is primarily localized in cardiomyocyte mitochondria and is a major source of reactive oxygen species (ROS). Here we assessed the role of NOX4 in ROS production and mitochondrial dysfunction in RV-overloaded infant hearts.
Methods: Newborn rabbits (n = 8/group, 10 days old) underwent pulmonary artery banding and serial function measurements (echo, P-V analyses). RV cellular and mitochondrial (Mito) fractions were isolated to assess Mito function, ROS generation, oxidative injury (8-OHdG and protein carbonyls) and NOX4 expression at 3, 4, and 8 weeks after banding (corresponding to early RVH, established RVH, and early RV failure, respectively).
Results: NOX-specific (NADPH-dependent and DPI-inhibitable) Mito ROS generation was detectable within 2 weeks of banding, prior to phenotypic or genotypic changes of RVH/RVF, increased Mito ROS from other sites, or evidence of electron transport complex (ETC) or Mito damage. Subsequently, NOX-4 expression and NOX-dependent ROS output continued to increase, followed by increased complex I-dependent ROS generation, decreased complex I activity, progressive ROS-mediated Mito damage and Mito dysfunction (Table), as well as cardiolipin oxidation, complex III dysfunction, and loss of Mito DNA (not shown).
Conclusion: Markedly increased NOX-4 expression and NOX-4-driven ROS generation are early and sustained features of infant RV pressure overload. These data also indicate that early up-regulation of NOX-4 initiates ROS-induced ROS generation by the Mito ETC, further exacerbating RV Mito damage and driving the progression of RVH to RVF.
- © 2012 by American Heart Association, Inc.